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Methotrexate

Methotrexate (abbreviated MTX; formerly known as amethopterin) is an antimetabolite drug used in treatment of cancer and autoimmune diseases. It acts by inhibiting the metabolism of folic acid. more...

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History

Methotrexate originated in the 1940s when Sidney Farber at Children's Hospital Boston was testing the effects of folic acid on cancer. That inspired chemists at the drug company Lederle to start looking for antimetabolites resembling folic. The result was methotrexate, which was developed in 1948. Methotrexate gained FDA approval as an oncology drug in 1953.

Uses

Methotrexate was originally used, as part of combination chemotherapy regimens, to treat many kinds of cancers. It is still the mainstay for the treatment of many neoplastic disorders including acute lymphoblastic leukemia.

More recently it has come into use as a treatment for some autoimmune diseases, including psoriasis, psoriatic arthritis, rheumatoid arthritis (see disease-modifying antirheumatic drugs), and Crohn's disease. In the case of rheumatoid arthritis, parallel use with infliximab or etanercept has been shown to markedly improve symptoms. (Klareskog, et al., 2004)

Although not licensed for this indication, methotrexate is also sometimes used (generally in combination with misoprostol) to terminate early pregnancies, particularly ectopic pregnancies.

It can be taken orally or administered by injection (intramuscular, intravenous or intrathecal). Although daily preparations are occasionally used, most patients take weekly doses, which decreases the risk of certain side-effects.

Adverse effects

Possible side effects can include anemia, neutropenia, increased risk of bruising, and nausea. A small percentage of patients develop hepatitis, while there is an increased risk of pulmonary fibrosis.

The higher doses of methotrexate often used in cancer chemotherapy can cause toxic effects to the rapidly-dividing cells of bone marrow and gastrointestinal mucosa. The resulting myelosuppression and mucositis are often prevented (termed methotrexate "rescue") by using folinic acid supplements (not to be confused with folic acid).

Methotrexate is a highly teratogenic drug and categorized in Pregnancy Category X by the FDA. Women must not take the drug during pregnancy, if there is a risk of becoming pregnant, or if they are breastfeeding. Men who are trying to get their partner pregnant must also not take the drug. To engage in any of these activities (after discontinuing the drug), women must wait until the end of a full ovulation cycle and men must wait three months.

There is a risk of a severe adverse reaction if penicillin is prescribed alongside methotrexate.

Mode of action

Methotrexate competetively and reversibly inhibits dihydrofolate reductase (DHFR), an enzyme that is part of the folate synthesis metabolic pathway. The affinity of methotrexate for DHFR is about one thousand-fold that of folate for DHFR. Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.

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Methotrexate vs. cyclosporine for widespread psoriasis - Tips from Other Journals
From American Family Physician, 3/1/04 by Bill Zepf

In patients with widespread psoriasis, treatment is difficult, and systemic medications often are required. The immunosuppressants methotrexate and cyclosporine can be used as treatments, but no head-to-head randomized trial has evaluated their relative efficacy. Heydendael and colleagues report on a comparative trial of the safety and efficacy of methotrexate versus cyclosporine for widespread psoriasis.

This study enrolled adult patients with moderate to severe psoriasis who had not responded well to treatment with ultraviolet B radiation and had not yet tried the study agents. Of the 111 patients initially screened, 88 were randomized. The most common causes for exclusion were liver abnormalities found on laboratory results or pretrial ultrasound screening. Trial participants were randomized to 15 mg of methotrexate once weekly given in three divided doses with a 12-hour interval between doses, or cyclosporine in a dosage of 3 mg per kg given in two daily doses. After four weeks, the study drug was increased in patients with less than a 25 percent reduction in psoriasis severity scoring. Methotrexate users were increased to 22.5 mg of the drug per week, while those assigned to cyclosporine were increased to a dosage of 5 mg per kg per day. Active treatment lasted for 16 weeks, followed by regular observation until one year after study entry.

Treatment had to be discontinued early in 12 patients taking methotrexate because of elevated liver enzyme levels, and in one patient taking cyclosporine because increased serum bilirubin levels and icterus were noted. Two patients developed hypertension while taking cyclosporine, but this condition was controlled with medication and slowly resolved after the treatment course was completed.

After 16 weeks of active treatment, the relative reduction in psoriasis severity scoring did not significantly differ between the group receiving methotrexate (64 percent improvement) and those taking cyclosporine (72 percent improvement). Complete remission of psoriasis was also similar between the two groups (40 percent of methotrexate patients and 33 percent of cyclosporine patients). The duration of remission after active treatment was short (an average of four weeks) and was similar in the two groups.

Minor side effects occurred in both groups, but they did not require dosage changes or discontinuation of the assigned treatment. Nausea was more common in methotrexate users (44 percent), while patients taking cyclosporine were more likely to have headaches (43 percent), muscle aches (29 percent), or paresthesias (33 percent). Quality-of-life scores were not significantly different in the two groups.

The authors conclude that methotrexate and cyclosporine have similar efficacy in the treatment of widespread psoriasis and are tolerated equally well.

Heydendael VM, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med August 14, 2003;349:658-65.

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